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The loss of dopaminergic neurons in Parkinson disease offers researchers an unsolved puzzle and a unique opportunity. The puzzler is why one precise group of neurons in the substantia nigra gradually dies. The opportunity is the chance to treat the disease by cell replacement, a focus of intense research. Some recent findings from Ronald McKay and colleagues from the National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, give insight into both, and provide a new mouse model for the disease.

Their work, published in the December 11 issue of PLoS Biology, identifies the transcription factor Foxa2 as a key regulator of both the birth and death of dopamine neurons in mice. Their study reveals a new driver for generating dopaminergic neurons in the lab from embryonic stem cells for replacement therapy (see ARF related news story). In addition, a heterozygous Foxa2 mutant mouse replicates several key features of Parkinson disease, including spontaneous, age-related and asymmetric neuron loss and motor abnormalities.

In the study, first authors Raja Kittappa and Wendy Chang find that expression of the forkhead family transcription factor Foxa2 is required for the development and maturation of dopaminergic neurons from precursors in the floor plate of the embryonic brain. In explants of embryonic brain from Foxa2-null mice, no dopamine neurons developed, but adding the factor by transfection triggered the appearance of tyrosine hydroxylase-positive dopaminergic neurons. Similar results were reported last summer (Ferri et al., 2007) by Siew-Lan Ang and colleagues from the MRC National Institute for Medical Research in London, who showed that Foxa2 is required throughout dopaminergic neuron development. The McKay group goes on to show that expressing Foxa2 in embryonic stem cells in vitro boosts the production of TH-expressing neurons.

Knocking out Foxa2 completely led to embryonic lethality, but heterozygote mice survived to adulthood. With aging, however, some developed motor abnormalities; their limbs turned rigid, they slowed down, and their spines curved. Such mice displayed amphetamine-induced rotation behavior, which is a signal of asymmetric dopamine neuron loss. The researchers confirmed this with immunohistochemistry, which revealed the loss of dopamine neurons preferentially in the substantia nigra. Spontaneous loss of neurons in an asymmetric pattern resembles the initial stages of human disease.

Mechanistically, too, the Foxa2 mice may be a better match to human disease than commonly used models of PD involving toxic ablation of neurons, the authors believe. The forkhead family of transcription factors controls cell survival downstream of the growth factor-induced PI3 kinase/Akt pathway, and plays a role in the response of cells to oxidative stress. Both factors have been repeatedly implicated in Parkinson disease. Thus, the Foxa2-deficient mouse may help us understand the progressive loss of neurons, and, eventually, how to prevent it.—Pat McCaffrey

Comments

The Foxa family of forkhead transcription factors—Foxa1, Foxa2, and Foxa3—play evolutionarily conserved and important roles in endodermal organ formation and function. Besides these developmental roles, Foxa transcription factors regulate glucose metabolism, homeostasis in adipocytes, longevity, and apoptosis in different organisms. More recently, Foxa transcription factors have come back into the spotlight with essential roles in the development of midbrain dopaminergic neurons. Loss of midbrain dopaminergic neurons of the substantia nigra (SN) subgroup is the hallmark of Parkinson disease.

We recently demonstrated that Foxa1 and Foxa2 have multiple and essential roles in the development of midbrain dopaminergic neurons in mice (1). Our data from phenotypic analyses of single and double Foxa1 and Foxa2 mutant embryos demonstrate that these genes function in a dose-dependent manner to regulate specification and differentiation of midbrain DA progenitors. Interestingly, results in this paper by Kittappa et al. suggest another role for Foxa2 in regulating survival of adult midbrain dopaminergic neurons. However, it remains to be determined whether and how Foxa2 functions cell- autonomously to regulate survival specifically of SN dopaminergic neurons.

Despite these unresolved issues, these two papers together demonstrate convincingly that Foxa1 and Foxa2 transcription factors are key determinants of dopaminergic neuron specification and differentiation in the midbrain and may facilitate the generation of dopaminergic neurons from human embryonic stem cells.